Immune responses decline with age, leaving the elderly more susceptible to infections such as influenza. B cell responses are correlated with a protective immune response in humans, and robust antibody responses are generally dependent on a strong CD4+ T cell response. In turn, CD4+ T lymphocytes are activated by foreign peptides presented in the context of major histocompatibility complex (MHC) class II molecules. The conversion of whole antigen to MHC-bound peptide is termed antigen processing. In the conventional model, class ll-binding peptides are generated in the late endosome via unfolding and/or proteolysis and subsequently loaded onto class II molecules with the assistance of the H-2M heterodimer. In contrast, the conventional pathway for MHC class l-restricted presentation to CD8+ T cells entails delivery of antigen to the cytosol where it is digested by the proteasome. The resultant peptides are transported to the endoplasmic reticulum by the TAP heterodimer where they are loaded onto empty, nascent class I molecules. This dichotomy has strongly influenced thinking in the field for many years. Recently we reported on two MHC class ll-restricted influenza epitopes that are presented via a pathway that is decidedly class I-like in that presentation depends upon cytosolic delivery, functional proteasome and the presence of TAP. Analysis of bulk class ll-restricted responses against influenza and vaccinia revealed that a substantial proportion is directed against proteasome-dependent epitopes. We have designed a research plan, a natural extension of our published studies, in order to 1) assess the degree to which proteasome-dependent CD4+ T cells contribute to the immune response and protection from viral challenge, and 2) understand how age-related changes in antigen processing pathways and subsequent CD4+ T cell activation contribute to the decreased immune responses in the elderly. Execution of the plan could lead to new insights on CD4 T cell priming, and provide novel mechanisms to improve influenza vaccine design for the elderly. Influenza is a significant public health problem in the United States, despite attempts to protect the population with yearly vaccination. As we age our immune systems become increasingly unable to protect us from infections, and viruses such as influenza become a major concern. The current vaccine for influenza is not an acceptable solution because the elderly respond poorly to it, and it often provides incomplete protection. The experiments we propose probe basic aspects of the immune response that may point to ways of increasing vaccine potency, a development that would be particularly beneficial to the elderly.